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Pharmacology and Medical Chemistry I > Exam 4 - Lecture 35, Cholinergic Agonists and Cholinesterase Inhibitors > Flashcards

Exam 4 - Lecture 35, Cholinergic Agonists and Cholinesterase Inhibitors Flashcards

1
Q

Direct Acting drugs

A

Agonist at muscarinic receptors (M type GPCRs)

Agonist at nicotinic receptors (nAChR ion channels)

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2
Q

Indirect acting drugs

A

Inhibitors of cholinesterase = increase ACh

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3
Q

M1, M3,M5

A

Gaq

Mechanism: IP3, DAG cascade

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4
Q

M2 or Cardiac M2

A

Gai/o

Mechanism: Inhibition of cAMP production, activation of K+ channels

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5
Q

M4

A

Gai/o

Mechanism: Inhibition of cAMP production

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6
Q

Nm and Nn ion channels

A

Mechanism: Na, K depolarizing ion channel

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7
Q

Nicotinic acetylcholine receptors

A

Pentameric channel, conducting Na,K,CA2+

Activation of receptor depolarizes membrane potential, initiating action potentials in neurons and contraction of muscle

Binding 1 ACh molecule results in modest increase in open probability; simultaneous binding gives significant increase in Po

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8
Q

Single nAChR channels

A

Fetal (immature) channels

Mature channels

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9
Q

Fetal (immature) channel

A

consists of 2 X a1 subunits and one each of beta, delta, and gamma-subunits. This channel has low amplitude currents with long open time

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10
Q

Mature channels

A

Gamma subunits are replaced with E-subunits.

Open time decreases but current amplitude increases

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11
Q

Whole-cell nAChR channels

A

some isoforms are pentamer of a7-subunits

activations results in fast, rapidly decaying currents

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12
Q

In response to continued activation, nAChR channels will….

A

Desensitize

Increase in Ca2+ will cause an increase in PKC (phosphorylates proteins that facilitate Desensitization of channels)

Active -> Desensitization -> resting state

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13
Q

Example action of activated nAChRs

A

Ach will bind to receptor, activate channel and they will pass Na and depolarize membrane…leads to EPSP (if large enough) and it will cause action potential and contraction

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14
Q

M1, M3, M5 detailed pathway

A
  1. Activates PLCB
  2. PLCB metabolizes PIP2 to DAG and IP3
  3. DAG activates PKC
  4. IP3 activates IP3 receptors on ER
  5. NOTE: decrease of PIP2 also has cellular effect (inhibition of M-current
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15
Q

M2 and M4 detailed pathway

A
  1. Gai inhibits Adenylate Cyclase -> decrease cAMP
  2. Gbg activates GIRK channels, made of Kir3-subunits, increase K+ flux and decrease excitability
  3. Gbg inhibits activity of specific Cav channels; decrease Ca2+ flux and decreasing excitability
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16
Q

Organophosphates

A

Irreversible , covalent inhibitors of AChE

most common type of chemical pesticide

Ex. DDT, banned by most countries in 70s and 80s and superseded by parathion

17
Q

Toxicity of direct & indirect cholinomimetic drugs

A

DUMBBELSS

D- diarrhea, defacation (muscarinic)
U- Urination (M)
M - Miosis (M)
B - Bronchospasm (M)
B - Bradycardia (M)
E - Excitation (N...followed by block)
L - Lacrimation (M)
S - Salivation (M)
S - Sweating (M)
18
Q

Medical use of cholinomimetic agents

A

Glaucoma
Ileus or Urinary retention
Myasthenia Gravis

19
Q

Glaucoma

A

often caused by high ocular pressure

Drugs constriction pupil and ciliary muscle, increasing outflow of humor form eye and reducing ocular pressure

20
Q

ILeus (Loss of peristaltic activity) or Urinary Retention

A

can occur after surgery or neurological injury

21
Q

Myasthenia Gravis

A

Autoimmune degradation of SM nAChRs, causing weakness treated with cholinesterase inhibitors

Short acting (15 min, used to diagnose)
Long-acting for treatment (4hr, neostigmine...8hr, pyridostigmine)
22
Q

Neostigmine

A

Used in treatment of Myasthenia graves

Used to treat Ogilvile syndrome

Used to treat envenomation from snake bite, particularly kraits

23
Q

Physostigmine

A

Reversible cholinesterase inhibitor

Used to treat glaucoma and delayed gastric emptying, mydiasis

Crosses BBB so can be used as antidote for OD with anticholinergics such as Atropine and Belladonna

Can cause death by respiratory arrest and paralysis of cardiac muscle

24
Q

Acetylcholinesterase enzymes

A

Found in high conc at chemical synapses and neuromuscular junctions

Required to terminate action of ACh

Inhibitors augment the action of ACh so are cholinomimics

Some AChE-inhibitors have medial utility, some are dangerous toxins

25
Q

Action of nicotinic cholinomimetics

A

Autonomic ganglia:
Both sympathetic and parasympathetic ganglia are activated; downstream action on innervated organs is unpredictable

SM neuromuscular junctions:
Depolarization due to opening of nAChR channels, causes muscle contraction. Maintained stimulation desensitizes nAChRs, leading to paralysis

26
Q

Action of muscarinic cholinomimetics on eye

A

contract pupillary constrictor and ciliary muscle; the pupil is biotic and focus is on near vision

27
Q

Action of muscarinic cholinomimetics on airway

A

contracts smooth muscle of airway, causing wheeing

28
Q

Action of muscarinic cholinomimetics on blood vessels

A

smooth muscle in most vessels has few cholinoreceptors; endothelium has M-receptors

if activated, endothelial cells produce NO, it diffuses into adjoining smooth muscle causing relaxation, BP falls and baroreceptors maybe evoked

29
Q

Action of muscarinic cholinomimetics on heart

A

Activation of vagal nerve causes bradycardia and slowed A-V conduction

Indirect cholinomimetics amplify effects of endogenous ACh

Direct cholinomimetics cause sufficient hypotension to evoke tachycardia

30
Q

Action of muscarinic cholinomimetics on exocrine gland

A

Lacrimal, salivary and thermoregulatory (eccrine) sweat glands stimulated

31
Q

Action of muscarinic cholinomimetics on GI and GU tract

A

smooth muscle contracts and motility increases, sphincters relaxed

32
Q

Recycling of GPCRs

A

Continued activation of GPCR can lead to B arresting binding which causes desensitization or internalization. It can be recycled back into membrane or it can be degraded

33
Q

Vagal regulation of the sinoatrial node

A

M2 receptors, coupled to Gai are activated when ACh is released by vagus nerve (parasympathetic)

Gbg is released and activates Kir3.1/3.4 (GIRK1/4) channels, hyper polarizing the membrane potential

Inhibition of adenylate cyclase reduces generation of cAMP -> decrease PKA -< decrease voltage gated Ca2+ current -> contraction

Decreased activation of HCN channels (funny current channels)

** Note: Activation of B-receptors -> Gas increases AC activity -> increase cAMP

34
Q

Gai and Gas often in complex together

A

Adenylate cyclase is in complex, trying to make cAMP with it being up and down regulated by Gai and Gas

Cholinergic (sympathetic)
M2 and M4 receptors are Gai coupled

Adrenergic (parasympathetic)
a2 adrenoceptors are Gai coupled
B1-3 adrenoceptors are Gas coupled

** M1, M3, M5, and a1 not couple to either Gai or Gas but to are coupled to Gaq **

Pharmacology and Medical Chemistry I (30 decks)

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